Many T cell based vaccines against human immunodeficiency virus (HIV) are in clinical trials. One promising study was canceled in 2007 after showing no evidence of protection, underscoring how little is known about the nature of protective T cell responses against HIV. We have discovered that Mauritian cynomolgus macaques (MCM) infected with simian immunodeficiency virus (SIV), a virus that causes the same disease as HIV causes in humans, offer unprecedented opportunities for understanding protective T cell responses. The distinguishing feature of MCM is their very simple genetics. This allows investigators to identify groups of animals who will mount predictable T cell responses against SIV and use these animals to advance our understanding of T cell immunity to HIV and SIV. We hypothesize that the HIV vaccines tested so far have not been successful at least partially due to their failure to elicit a broad repertoire of T cell specificities. It is difficult to test this hypothesis in humans, so we will test this hypothesis in SIV+ MCM, taking advantage of their simple genetics. These experiments rely on groups of MCM that are either homozygous or heterozygous for major histocompatibility complex (MHC) class I genes that present SIV-derived peptides to T cells. We predict that MHC heterozygous MCM have the capacity to present twice as many peptides to T cells as MHC homozygous MCM when challenged with pathogenic strains of SIV, and therefore are more likely to control infection with this AIDS virus. First, we will infect MHC homozygous and heterozygous MCM with pathogenic SIV and monitor SIV disease progression, the number of recognized T cell epitopes, and virus evolution. We anticipate that MHC homozygous animals will recognize fewer SIV CD8+ T cell peptides than MHC heterozygous MCM, and that this will result in higher viral burdens in the homozygous animals. Next, we will produce a strain of SIV where the T cell epitopes that are normally recognized during SIV infection are knocked out and ask whether this virus can be effectively controlled by the immune systems of MCM. Lastly, we will immunize MCM with a weakened vaccine strain of SIV that elicits potent immune responses. The MCM will be challenged with the knockout strain of SIV that does not contain specific T cell epitopes. Since the vaccine and challenge viruses will differ primarily within defined T cell epitopes, this experiment will determine how important broadly directed T cell responses are to the impressive control afforded by attenuated SIV. Taken together, these experiments will fundamentally advance our understanding of the importance of T cell breadth in control of HIV and SIV, and help determine whether eliciting a broad CD8+ T cell repertoire should be a major goal for HIV vaccines. Researchers still do not know what sorts of immune responses might protect people against AIDS. In this work, we will use a unique animal model to determine whether the ability to mount diverse cellular immune responses against multiple targets within the AIDS virus influences the ability of infected individuals to control virus replication.